tbuckley/cabot-search huggingface dataset:
TMIC-41. LATERAL VENTRICLE PROXIMITY OF GLIOBLASTOMA IS ASSOCIATED WITH LOCALIZED MALIGNANCY-PROMOTING MOLECULAR SIGNATURES IN IMAGE-GUIDED BIOPSIES
Authors: Emily Norton, Andres Ramos-Fresnedo, Yesesri Cherukuri, Lauren Whaley, Paula Schiapparelli, Yan Asmann, Kaisorn Chaichana, Alfredo Quiñones-Hinojosa, Hugo Guerrero-Cazares
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most devastating and common form of primary brain cancer in adults. Tumor location plays a significant role in patient prognosis; in particular, GBM tumors contacting the lateral ventricles (LVs) are more aggressive than LV-distal counterparts. This may be due to interaction of tumors with unique features of the LV microenvironment, including the cerebrospinal fluid (CSF) and neural progenitor cells (NPCs) of the subventricular zone. Despite LV contact having a role on tumor malignancy, studies using bulk tumor samples to identify molecular contributors to LV-contacting prognosis have been only moderately successful, in large part due to intratumoral heterogeneity. Here, we leverage intraoperative surgical navigation to collect matched biopsies of adult LV-contacting primary GBM at locations proximal (&amp;lt; 2 cm) and distal ( &amp;gt; 2 cm) from the LV. Matched samples were collected from ten patients with equal sex distribution and an age range of 46 to 81 years. RNA sequencing of biopsies revealed a localized transcriptional signature of gene expression in LV-proximal locations. These genes include those identified to be associated with GBM malignancy and upregulated in primary GBM cells by CSF exposure or co-culture with NPCs, such as SERPINA3, CD44, and CTSB, as well as many newly identified genes. Implicated biological pathways involved in this transcriptional signature involve inflammation, chemotaxis, Notch signaling, angiogenesis, integrin signaling, and more. The top 50 upregulated genes by LV-proximity of GBM were used to cluster patient transcriptomes from the TCGA GBM database and evaluate the contribution to patient outcome. This analysis revealed a cluster with significantly extended overall survival that displayed a general downregulation of LV-proximity genes. Ultimately, these studies provide evidence that regional tumoral analysis is essential in identifying molecular signatures associated with microenvironmental influence, and that LV-contacting GBM has regional gene expression changes in many genes associated with malignancy.
SURG-12. MANAGEMENT OF ATLANTOAXIAL INSTABILITY IN THE SETTING OF CLIVAL CHORDOMA WITH EXTENSION TO THE CRANIOCERVICAL JUNCTION: A COMPREHENSIVE REVIEW OF CLINICAL MANAGEMENT
Authors: Nolan Brown, Basel Musmar, Oanh Nguyen, Cathleen Kuo, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Clival chordomas that involve the craniovertebral junction (CVJ) are particularly challenging to remove due to risk for postoperative atlantoaxial instability. Preoperative instability can also be present due to mass effect from the clival lesion. Surgery involves a delicate balance of acknowledging existing preoperative instability, when present, and aiming for gross total resection (GTR) while determining the optimal time to fuse occiput to axial spine. This requires extensive knowledge of operative anatomy, neuro-oncology, and spinal biomechanics. Method Adhering to PRISMA guidelines, we examined all currently available neurosurgical literature pertaining to skull base chordomas with extension to the craniocervical junction. RESULTS Thirty studies featuring 435 patients (age range: 2-78 years) were identified, including 14 retrospective cohort studies, 6 case reports, and 3 case seriesdescribing surgical management with OCF. The remaining 7 studies (4 retrospective cohort studies and 3 case reports) reported surgical management without OCF. Our findings indicate that cervical instability due to the fracture or loss of the odontoid process in the pediatric population is an indication for OCF. With respect to timing, it appears that OCF can be conducted prior to or following tumor resection if there is clinical suspicion that a patient will eventually develop atlantoaxial instability (odontoid process removal is an indication for OCF). CONCLUSION OCF is indicated for patients when concern for craniocervical instability exists. Although it can be performed following surgical chordoma resection, as long as such instrumentation does not interfere with achieving surgical goals of GTR and/or maximal safe resection, results suggest that optimal outcomes may be obtained when OCF precedes tumor resection. In addition to the degree of instability present, brian stem compression, extent of resection, and amount of instrumentation to be performed are factors that should be discussed between a skull base surgeon-spine surgeon multidisciplinary team.
SURG-13. PEDIATRIC PRIMARY CENTRAL NERVOUS SYSTEM NEOPLASMS: RELATIVE UTILITY OF OPEN, MULTI-STAGE CRANIAL SURGERY
Authors: Nolan Brown, Nicholas Bui, Cathleen Kuo, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE Staged surgery for skull base lesions has been utilized to facilitate maximal safe resection and optimize outcomes in pediatric patients. Despite its extensive applications, there is a paucity of information regarding open multi-stage resection of intrinsic, intra-axial neoplasms. We reviewed the literature in order to shed light on relevant considerations including the timing between surgeries, indications for staged approaches, and clinical outcomes following staged resection of pediatric intra-axial neoplasms. METHODS We conducted a literature search using PubMed, Web of Science, and Cochrane databases according to PRISMA recommendations. RESULTS Of 115 results, 7 articles were included for final analysis and consisted of 17 pediatric patients, including 6 (35%) male, 5 (29%) female, and 6 (35%) unspecified sex patients. Age ranged from 18 months to 17 years (mean 9 years). Tumor pathologies consisted of 5 (29%) astrocytomas, 2 (12%) ependymomas, 2 (12%) teratoid rhabdoid tumors, 2 (12%) oligodendromas, 1 (6%) glioma, 1 (6%) dysembryoplastic neuroepithelial tumor, 1 (6%) meningioangiomatosis, 1 (6%) pleomorphic xanthoastrocytoma, 1 (6%) ganglioglioma, and 1 (6%) germ cell tumor. Primary sites of the tumor included 4 (24%) temporal lobe, 3 (18%) thalamic, 3 (18%) thalamopeduncular, 3 (18%) frontal lobe, 2 (12%) posterior fossa, 1 (6%) cerebral hemisphere, and 1 (6%) frontoparietal lobe. Three studies reported complications, which included subtle hemiparesis, hydrocephalus, cranial nerve (CN) VI and VII palsies, truncal ataxia, and cerebellar mutism. Timing between surgeries varied from 5 days to several weeks CONCLUSION Indications for performing multi-stage resections included large tumor volume requiring multiple long stages of debulking, significant tumor vascularity, multicompartmental lesions, and planned staging due to presence of large tumors requiring resection around eloquent speech and motor cortical and white matter tract lesions that enabled use of awake functional mapping after a primary debulking performed in proximity to less eloquent regions.
NIMG-10. A MRI-BASED RADIOMICS MODEL PREDICTING DNA DAMAGE REPAIR GENES EXPRESSION SUBTYPES AND PROGNOSIS IN GLIOBLASTOMA
Authors: Mingwei Zhang, Yufan Wu, Xiaoxia Li, Xuezhen Wang, Shan Li, Jinsheng Hong
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is the most common primary brain tumor, with a dismal prognosis. Some DNA Damage Repair (DDR) pathways are related to progression and worse prognosis in GBM patients. However, the association between overall expression levels of DDR genes and prognosis for GBM has not been reported. Radiomics has become an essential tool for assessment of clinical information in GBM patients, expected to be a noninvasive tool for predicting DDR genes expression and prognosis. METHODS The TCGA database was used to obtain the GBM patients imaging, clinical and RNAseq data. We screened DDR genes and clustered them into subgroups based on their expression status, and determined differences between subgroups in prognosis and molecular mechanisms. Radiomics model based on MRI CE-T1 image was investigated to predict DDR subgroups and the output was defined as the radiomics score (RS). Prognosis analysis of RS and traditional clinical indicators was performed in TCGA cohorts, and external validated in 2 medical centers. RESULTS A total of 156 individuals with GBM were identified from the TCGA cohorts. 140 genes were screened in DDR gene libraries, which were classified into 2 clusters. Survival analysis showed that overall survival (OS) was significantly higher in DDR suppression subgroup than activation subgroup (21.1 vs 14.9, p=0.001), and differences in immune microenvironment, biologically active pathways were observed in the 2 groups. A model composed of 4 radiomics features were built, which can distinguish 2 DDR subgroups. RS was an independent protective factor for OS (HR=0.630, 95%CI=0.400−0.992, P=0.046). The result was externally validated by two cohorts.
SURG-22. MECHANISMS OF BBB PERMEABILITY CHANGES TRIGGERED BY LASER THERAPY
Authors: Ryan Cleary, Albert Kim
Journal: Neuro-Oncology (2023)

Abstract The blood-brain barrier (BBB) severely limits access of systemically delivered drugs to the brain and brain tumors. Laser interstitial thermal therapy (LITT) has previously been shown to increase BBB permeability in both patients and in mice. The exact mechanisms of LITT-induced BBB permeability changes and their temporal features have yet to be elucidated. To answer this question, we used an established mouse model of LITT to evaluate changes in endothelial cell tight junction integrity and transcytosis over time in normal brain and demonstrate changes in transcytosis in human GBM tumor samples. Mean vesicular density (MVD) was calculated using electron microscopy to evaluate transcytosis. Immunohistochemistry (IHC) was used to assess tight junction integrity (Claudin 5 area/CD31 area) and Mfsd2a levels (Mfsd2a area/CD31 area) along endothelial cells in the laser penumbra. Tight junction integrity decreased 2.5 fold 3 days after LITT, with continued decrease 14 days post-LITT. Mean vesicular density (MVD) in endothelial cells within the laser penumbra increased 3-4 fold compared to sham treated mice, with a peak increase 14 days after LITT before returning to baseline levels 21 days after treatment. These changes in transcytosis correlated with a significant decrease in the intensity of Mfsd2a IHC in the laser penumbra at day 14. Finally, we found similar low levels of transcytosis in non-enhancing and enhancing human GBM tumor samples, confirming that transcytosis is potentially targetable to manipulate BBB permeability. CONCLUSION: Disruptions in tight junction integrity continue up to 14 days after LITT, while LITT-induced increases in transcytosis occur in a delayed fashion, peaking 14 days after laser treatment. Increased transcytosis is inversely correlated with decreased Mfsd2a expression, suggesting a role for Mfsd2a in regulation of LITT-induced BBB changes. Importantly, baseline levels of transcytosis in human GBM appear to be low, such that transcytosis could be targeted to increase BBB permeability.
NIMG-70. TRACKING CELLULAR SOCIAL BEHAVIOR OF PATIENT-DERIVED PRIMARY CELL LINES TO GATHER NEW INSIGHTS FOR BETTER STRATIFICATION OF GLIOBLASTOMA PATIENTS
Authors: Gianmarco Ferri, Mariangela Morelli, Francesca Lessi, Sara Franceschi, Francesco Pieri, Carlo Gambacciani, Paolo Aretini, Francesco Pasqualetti, Orazio Santo Santonocito, Anna Luisa Di Stefano, Chiara Maria Mazzanti
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma is one of the most frequent and aggressive brain tumors. The average life of these patients is on average less than 15 months, due to the proliferation and invasiveness of the tumor cells, which not only constitute the tumor mass but which also infiltrate the normal parenchyma brain to form new cancerous sites. Knowing the specific behavior of the cell types that make up the tumor of every single patient, in terms of volume, shape, motility, and cell-cell interaction could be informative for patients’ tumor stratification. Here we developed a protocol that integrates imaging and image processing algorithms, to accurately and quantitatively identify the morphological and behavioral characteristics of tumor cells cultured in vitro and track their movement over time. This approach enables quantifying important biological processes such as cell migration and cell growth, both of which play a major role in the development of diseases. The cell tracking method combines segmentation methods with spatiotemporal optimization to analyze microscopy images. The method also determines various information about cell movements such as movement paths, speed, and distance covered. Knowing the behavior of the malignant glioma cells of a specific patient, in terms of shape and motility (e.g. direction and speed of movement), also in relation to other cells could be informative in the context of dynamic precision medicine. In this context, we created a model that integrates the characteristics of each patient's tumor cells and provides a new way of stratifying patients that can be correlated with clinical data.
MODL-49. NEW MURINE GLIOBLASTOMA STEM-LIKE CELL MODELS
Authors: Kimia Kardani, Shanawaz Mohammed Ghouse, Toshiro Hara, Yasushi Soda, Anat Stemmer-Rachamimov, Hiroaki Wakimoto, Samuel Rabkin
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND There is a dearth of mouse glioblastoma (GBM) preclinical models in immunocompetent mice for the development of immunotherapeutic agents. In this study, we characterized five murine GBM stem-like cell (GSC) models derived from lentivirus induced tumors in transgenic mice that are driven by the activation of the Nf1-Ras MAP kinase signalling pathway due to HRasV12 or NF1 shRNA, and inactivation of Tp53. METHODS Murine GSC lines, 005, NF53, RIG, C1, and C3, were cultured as spheres in serum-free stem cell media. Whole exome sequencing (WES) was conducted to quantify single nucleotide polymorphisms (SNPs) using the C57BL/6J genome as reference. Stem cell properties were characterized by in vitro assays and tumorigenicity was examined by intracerebral implantation into C57BL/6 mice. Brain tissues were processed for histological analysis, such as immunohistochemistry, or for FACS to examine markers of stemness and tumor-infiltrating immune cells. RESULTS WES identified a large variation in coding sequence SNPs, likely due to the mixed backgrounds of the parental mice, with 005 having the highest number of SNPs, and C1 and C3 the lowest. All GSC lines were capable of clonogenic sphere formation, indicative of self-renewal, and showed varying levels of cell surface CD133. In vivo, all the GSCs efficiently established tumors that were histologically consistent with malignant glioma with strong CD44 expression. Median survival varied, ranging from 27 days (005) to 82 days (C1), upon 20,000-cell implantation. CD68+ macrophages were consistently dominant in the tumor microenvironment, while C1 and C3 exhibited fewer CD4+ and CD8+ T cells. CONCLUSIONS Despite the similar molecular strategy used to generate these GBMs, we observed a range of tumor phenotypes and immune microenvironmental profiles. These models can serve as valuable tools for studying GBM biology and exploring immunotherapeutic strategies. Keywords: Glioblastoma, glioblastoma stem-like cell (GSC), genetically engineered mouse models, Tumor microenvironment.
TMIC-11. SPATIAL PROFILING OF TUMOR VASCULATURE AT AUTOPSY IN BRAINSTEM GLIOMAS
Authors: Joelle Straehla, Jared Woods, Jayne Vogelzang, Jacquelyn Jones, Keith Ligon, Sanda Alexandrescu
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Diffuse midline glioma (DMG) is a lethal pediatric tumor, and new treatment strategies are urgently needed. To design therapies that can cross the blood-tumor barrier, we designed a pilot study to investigate protein expression on DMG tumor vasculature using spatial profiling, with attention to targetable surface proteins. METHODS We identified 5 patients and 4 controls consented to institutional tissue banking protocols with adequate autopsy tissue from multiple anatomical regions within the brainstem. Portions of formalin-fixed, paraffin-embedded tissue were arranged into tissue microarrays profiled using the nanoString GeoMX platform. Briefly, a multiplexed cocktail of 51 primary antibodies tagged with UV-photocleavable oligonucleotide barcodes and fluorescent morphology markers were applied to tissues and 10-14 regions of interest (ROIs) were segmented by vessel area for each patient. ROIs were processed using UV light and barcodes were quantified using ex situ digital counting. RESULTS Five patients were included in the pilot study with average age 9.8 years (range 8-13), and overall survival was 9.5 months (range 3-18 months). Three tumors were classified as DMG, H3K27-mutant, WHO grade 4; one as high grade glioma without identified histone alteration but with recurrent DMG drivers (ACVR1 and PIK3CA mutations) and one as infiltrating atypical glioma with high proliferative rate and no DMG driver mutations. Controls ranged from 4-15 years and did not have pathological changes in the brain at death. Protein abundance was compared between cases and control and within cases where tumor-adjacent normal tissue was identified. Several proteins were significantly more abundant on tumor vasculature compared to non-tumor adjacent or control brainstem vessels. Validation studies in primary tissue are ongoing. CONCLUSIONS Digital spatial profiling is a promising technology for investigating tumor vasculature and is feasible in autopsy specimens. Work is ongoing to validate candidate biomarkers and expand the cohort to develop a vascular atlas for DMG.
BIOM-55. TARGETED GENE EXPRESSION PROFILING PREDICTS MENINGIOMA OUTCOMES AND RADIOTHERAPY RESPONSES
Authors: William Chen, Abrar Choudhury, Mark W Youngblood, Mei-Yin Polly, Calixto-Hope Lucas, Kanish Mirchia, Sybren Maas, Abigail Suwala, Minhee Won, James Bayley, Akdes Harmanci, Arif Harmanci, Tiemo Klisch, Minh Nguyen, Harish Vasudevan, Katy McCortney, Tai-Chung Lam, Jenny Kan-Suen Pu, Lai-Fung Li, Gilberto Ka-Kit Leung, Jason Chan, Haley Perlow, Joshua Palmer, Anna Berghoff, Matthias Preusser, Theodore Nicolaides, Christian Mawrin, Jacob Young, Lauren Boreta, Steve Braunstein, Jessica Schulte, Nicholas Butowski, Sandro Santagata, Nancy Ann Oberheim Bush, Javier Villanueva-Meyer, James P Chandler, David Solomon, Leland Rogers, Stephanie Pugh, Minesh Mehta, Penny Sneed, Mitchel Berger, Craig Horbinski, Michael McDermott, Arie Perry, Wenya Linda Bi, Akash Patel, Felix Sahm, Stephen Magill, David Raleigh
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Here we report multicenter clinical and analytical validation of a gene expression biomarker using clinical and genomic data from 1856 meningiomas from 12 institutions across 3 continents. METHODS A previously-developed 34-gene expression biomarker was applied to 3 validation cohorts: (1) a multicenter retrospective clinical validation cohort (N = 6 centers, N = 866 meningiomas, median follow-up 5.2 years), (2) a prospective investigator-blinded clinical validation cohort from RTOG 0539 (N = 103 meningiomas, median follow-up 8.4 years), and (3) an analytical validation cohort for test/re-test and FFPE/frozen analyses, and comparison across platforms for gene expression quantification (N = 8 centers, N = 1219 meningiomas). Biomarker performance was compared to 9 other meningioma classification systems. Favorable versus unfavorable cases were defined as (1) gene expression low risk with any resection, or gene expression intermediate risk with GTR (favorable), versus (2) gene expression intermediate risk with STR, or gene expression high risk with any resection (unfavorable). RESULTS The biomarker improved on WHO 2021 grade (5-year local freedom from recurrence [LFFR] delta-AUC 0.11, 95% CI 0.07-0.17, p&amp;lt; 0.001) and all other classification systems for LFFR and OS on multivariate analysis, achieving a negative predictive value for recurrence at 5-years of 91.9%. The biomarker predicted LFFR after postoperative radiotherapy, with a hazard ratio of 0.33 for unfavorable primary WHO grade 2 meningiomas (95% CI 0.14-0.76, P = 0.009), and 0.54 for unfavorable propensity-matched meningiomas across all WHO grades (95% CI 0.37-0.78, p = 0.0001). The biomarker reclassified 39.8% of meningiomas from RTOG 0539, including downstaging 30.5% of patients who received postoperative radiotherapy, and was independently prognostic for overall survival on multivariate analysis. CONCLUSIONS A 34-gene expression biomarker improves prognostication of meningioma outcomes and predicts postoperative radiotherapy responses.
BIOM-52. PROTEOMIC PROFILE OF CEREBROSPINAL FLUID IN MEDULLOBLASTOMA AND THEIR RELATED EXTRACELLULAR VESICLE PROTEIN
Authors: Seung Ah Choi, Joo Whan Kim, Kisoon Dan, Saehim Ha, Ji Hoon Phi, Dohyun Han, Seung-Ki Kim
Journal: Neuro-Oncology (2023)

Abstract The development of a sensitive diagnostic method for medulloblastoma (MBL), a common malignant brain tumor in children, is still a challenge. Cerebral spinal fluid (CSF) contains various substances such as soluble proteins and extracellular vesicles (EVs) and may reflect pathological changes in the central nervous system. Especially, EVs within CSF have great potential in the dynamic monitoring and intervention strategies of MBL. This study attempted to determine whether the total CSF protein selected based on proteome information distinguished from the CSF in MBL is also considered in EVs cargo proteins. CSF samples from patients with MBL (N = 44) and hydrocephalus (HC, control, N = 18) were analyzed with LC-MS. A machine-learning approach was used to identify protein biomarkers discriminating MBL CSF. The biomarker potential of the selected proteins was verified through ELISA and ROC analysis. TEM, Nanosight, and Exoview systems were used to analyze the physiological and biological characteristics of proteins in EVs from MBL CSF. Proteomic analysis revealed four elevated soluble proteins (Transketolase (TKT), SPTBN1, HSP90AA1 and NME1-NME2) in MBL CSF. Verification of the selected proteins in whole CSF confirms that TKT was significantly elevated in MBL than in HC. Importantly, the AUC value of TKT was 0.94, which was recognized as an excellent diagnostic marker. In additional TKT analysis, when MBL was divided into subtypes, Group 4 was the most significant compared to HC, and when divided into metastasis group, metastasis was more significant than non-metastatic compared to HC. Consistently, TKT was more abundant in MBL CSF EVs compared to HC CSF EVs. Our results provide insights into the relevance of the proteins in CSF to the cargo proteins reflected in EVs, while also proposing TKT in CSF EVs as an MBL diagnostic marker.